TNF-α Gene Promoter Research Articles

Meta-analysis: the relationship between TNF-alpha polymorphisms and susceptibility to primary biliary cirrhosis.

To investigate the possible influence of TNF-α gene promoter polymorphisms in conferring a predisposition to PBC patients. We performed a meta-analysis of nine articles searched from PubMed up to July 2010 that investigated the association between two TNF-α polymorphisms (-308 and -238) and PBC. The data showed no significant association between TNF-α-308, -238 gene polymorphisms and the susceptibility to PBC in the global group (OR=0.95, 95%CI=0.80-1.13, p=0.55; OR=1.00, 95%CI=0.65-1.55, p=0.99, respectively). Stratified by sub-groups (European, American, Asian), TNF -308 minor allele, but not -238, was found to be a protective factor in the European population (OR= 0.81, 95%CI=0.67-0.99, p=0.04; OR=0.99, 95%CI=0.55-1.77, p=0.97, respectively). Moreover, no significant difference was observed between TNF-α-308 alleles and PBC when stratified by histological stages (stages I-II, OR=0.68, 95%CI=0.32-1.48, p=0.33; stages III-IV, OR=0.69, 95%CI=0.41-1.15, p=0.15). TNF-α promoter polymorphisms might not be associated with PBC risk. However, studies with larger population of varying ethnicity and stratified by clinical and laboratory characteristics are needed to validate our findings.

Determination of the Cytokine Gene Polymorphism and Genetic Susceptibility in Tuberculosis Patients

Tuberculosis (TB) is a complicated disease in which biological, socioeconomical and environmental factors play role. Since only 10% of the individuals infected with Mycobacterium tuberculosis develop active disease, it has been suggested that host genetic factors may influence the risk for the development of TB. In this study, we aimed to investigate the presence and role of single nucleotide polymorphisms in the gene regions responsible for cytokine production, since these factors are considered to be associated with susceptibility or resistance to disease development. Single nucleotide polymorphisms were investigated by Amplification Refractory Mutational System (ARMS) Polymerase Chain Reaction (PCR) and PCR-Restriction Fragment Length Polymorphism (RFLP) methods. The presence of single nucleotide polymorphisms were analyzed in tumor necrosis factor alpha (TNF-α) gene promoter -308 G>A (rs1800629) region, interferon gamma (IFN-γ) gene +874 T>A (rs61923114) region, interleukin (IL)-12B p40 gene 1188 A>C (rs3212227) region, IL-10 gene promoter -1082 G>A (rs1800896) region and IL-4 gene promoter -590 C>T (rs2243250) region. A total of 84 patients (71 male, 13 female; mean age: 32.57 ± 15.94 years) whose clinical samples yielded M.tuberculosis complex growth, and 110 healthy blood donors (93 male, 17 female; mean age: 29.40 ± 11.56 years) as control group were included in this study. Of the patients, 76 (90.5%) were diagnosed as pulmonary and 8 (9.5%) as extrapulmonary TB. While 79 (94.1%) patients were newly diagnosed as TB, 5 (5.9%) patients had a TB history (relapsed TB). It was detected that acid-fast bacilli (AFB) were positive in 58 (69%) patients. According to the single nucleotide polymorphism results, gene frequencies could not be compared for TNF-a gene promoter -308 G>A region since healthy controls were in Hardy-Weinberg equilibrium while the patients were not. There were no statistically significant differences in allele and genotype distribution between the patients and healthy controls in IFN-γ gene +874 T>A region, IL-12B p40 gene 1188 A>C region, IL-10 gene promoter -1082 G>A region and IL-4 gene promoter -590 C>T region (p> 0.05). There were also no statistically significant differences between AFB positive (n= 58) and negative (n= 26) patients, and AFB positive (n= 56) and negative (n= 20) pulmonary TB patients (p> 0.05). In conclusion, no statistically significant differences were found associated with the susceptibility or resistance to TB with single nucleotide polymorphisms in the gene regions responsible for cytokine production in the study population. Only some of the single nucleotide polymorphisms of the gene regions responsible for cytokine release were investigated in our study. Therefore further detailed studies to investigate the polymorphisms in the genes that control the cytokine release and receptors specific for these cytokines, should be conducted. Although this study was performed in a relatively small sized population, these findings might provide a significant contribution to the epidemiologic data about the molecular immunology of TB in Turkey.

Genetic polymorphisms of tumour necrosis factor alpha (TNF‐α) promoter gene and response to TNF‐α inhibitors in Spanish patients with inflammatory bowel disease

Tumour necrosis factor alpha (TNF-α) has an important role in inflammatory response. Alterations in the regulation of TNF-α have been implicated in a variety of inflammatory disorders, including Inflammatory bowel disease (IBD). Indeed, a common treatment for IBD is the use of TNF-α inhibitors. Polymorphisms in the TNF-α promoter region are known to affect the level of gene expression. Our aim was to investigate the influence of these single nucleotide polymorphisms (SNPs) in TNF-α promoter gene play in the risk of IBD in a Spanish population and their individual response to anti-TNF-α treatment. DNA samples from patients with IBD and controls were screened for TNF-α -238G/A (rs361525) and -308G/A (rs1800629) SNPs by PCR-SSOP using a microbeads luminex assay and compared with response to TNF-α inhibitors. There were not statistical differences in -238G/A and -308G/A allele and genotype frequencies between patients. However, we found an increased frequency of -308A allele and -308GA genotype in these nonresponders patients to TNF-α inhibitors with respect to responders patients (Pc<0.05). This -308GA genotype has been classified as high producer of this cytokine. This fact could actually be interesting to explain the different response of patients with IBD with respect to TNF-α inhibitors. TNF-α promoter gene polymorphism does not seem to play a role in IBD susceptibility, but particular TNF-α genotypes may be involved in the different responses to TNF-α inhibitor treatment in Spanish patients with IBD.

TNF-α polymorphisms and coronary artery disease: Association study in the Korean population

Coronary artery disease (CAD) results from atherosclerosis, a chronic inflammatory disease mediated in part by proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α), which is expressed by atherosclerotic plaques. In this study, we investigated whether TNF-α gene promoter polymorphisms affect the incidence of CAD in Koreans by genotyping. 404 Control subjects and 197 patients who previously received a coronary artery stent for the G/A, C/T, and C/A polymorphisms at position −238, −857 and −863, respectively. The G/G, G/A and A/A genotypes at position −238 occurred in 85.8%, 14.2% and 0% CAD patients and 91.8%, 7.9% and 0.3% control subjects, respectively. The G/A polymorphisms at position −238 were significantly associated with CAD when assuming a dominant model of inheritance (OR=1.87; 95% CI=1.10–3.20; P=0.02), and A allele carriers had a significantly increased risk of developing CAD relative to the G allele (OR=1.74; 95% CI=1.04–2.92; P=0.03). However, the polymorphisms at positions −857 and −863 were not associated with CAD. Haplotype-based analysis revealed the CAD and control groups differed significantly in the frequencies of haplotype ACC at positions −238, −857 and −863 (OR=1.77; 95% CI=1.05–2.98; P=0.03). This was confirmed by multivariate analysis after adjusting body mass index and the presence of diabetes and hypertension (OR=2.06; 95% CI=1.15–3.68; P=0.015). Thus, the −238A allele of TNF-α is associated with an increased risk of CAD and could be used as predictor for CAD in Koreans. Further studies are needed to elucidate the clinical implications of these findings.

Association Analysis Between –308G/A and –238G/A TNF-Alpha Gene Promoter Polymorphisms and Insulin Resistance in Mexican Women With Gestational Diabetes Mellitus

BackgroundGestational diabetes mellitus (GDM) is characterized by insulin resistance. It has been described that tumor necrosis factor α (TNF-α) plays a key role in the pathogenesis of insulin resistance; moreover,...

Tumor necrosis factor (TNF)-α gene +489 polymorphisms: association with psoriatic arthritis

Objective of this work was to investigate the role of single nucleotide polymorphisms (SNPs) at position +489 of the tumor necrosis factor (TNF)-α gene in generic susceptibility and severity of psoriatic arthritis (PsA). Fifty-seven Caucasian PsA patients diagnosed according to CASPAR criteria and 155 healthy matched controls were studied. PASI score, DAS28 and Disability INdex HAQ were calculated. Genomic DNA was extracted from peripheral blood samples and SNPs +489 G&amp;gt;A (rs 80267959) were amplified by PCR. The SNP +489 genotype was significantly associated with PsA susceptibility (p=0.0136) and severity of clinical and laboratory parameters (p values ranging from 0.016 to 2.908 x 10-12). The difference in severity was accounted for by the difference between the AA and GA genotypes with respect to the GG genotype. These findings suggest that TNF-α gene polymorphisms may influence PsA susceptibility and severity. Psoriatics arthritis (PsA) is a complex immunemediated disease that results from the interplay between multiple genetic and environmental factor [1]. Although the pathogenesis of PsA remains elusive, there is evidence that genetic factors may contribute to the etiology of the disease [2]. Is has been estimated that at least one third of the genetic contribution to PsA resides in the major histocompatibility complex (MHC) region [2]. The tumor necrosis factor (TNF)-α gene, which is located in the short arm of chromosome 6 in the MHC class III region between the HLA-B and HLA-DR genes, has been proposed as a major candidate gene in PsA [3]. This hypothesis is supported by studies which have found high serum, synovial fluid and synovial membrane TNF-α levels in patients with PsA [4,5]. Several single nucleotide polymorphisms (PNPs) have been identified in the TNF-α gene promoter [6]. In particular, two common polymorphisms, namely G to A substitutions at positions -238 and -308 have been studied in patients with PsA. However, association studies of these two TNF-α polymorphisms and genetic susceptibility to PsA have lead to conflicting results [7-12]. Previous studies have indicated the potential role of the SNP at +489 position in the first intron of the TNF-α gene in the susceptibility to some rheumatic autoimmune diseases like rheumatoid arthritis [13], systemic lupus erythematosus [14] and systemic sclerosis [15]. However, to our present knowledge, studies on the association of +489 polymorphism with PsA susceptibility and response to TNF-α inhibitors are not reported in the literature. Is this study we investigated the role of SNPs at +489 within the TNF-α gene in PsA susceptibility and severity.

Association between pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections disease and tumor necrosis factor-α gene−308 g/a, −850 c/t polymorphisms in 4-12-year-old children in Adana/Turkey

OBJECTIVES:Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is a newly defined disease in neuropsychiatry and occurs with an autoimmune mechanism after Group A Beta Hemolytic Streptococcus (GABHS) infection. Tumor necrosis factor (TNF), encoded by TNF-α gene has an important role in the apoptotic mechanisms of autoimmune diseases. Recently, TNF-α polymorphisms and autoimmune/psychiatric disorders have been reported to be related. In this regard, we focused on to investigate a possible relation between the TNF-α gene promoter region−308 G/A and − 850 C/T polymorphisms and PANDAS.MATERIALS AND METHODS:In this study, ages of PANDAS patient and control groups were ranging from 4 years to 12-year-old. Patient group includes childhood onset PANDAS patients (n = 42) and control group includes healthy children (n = 58). Diagnoses have been carried out according to Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria with Affective Disorders and Schizophrenia-Present and Lifetime (KSAD-S-PL) and Children Yale-Brown Obsessive Compulsive Scale Moreover, PANDAS criteria established by the American National Psychiatry Institute have been employed for diagnoses. For identifying polymorphisms; Polymerase Chain Reaction, Restriction Fragment Length Polymorphism and Polyacrylamid Gel Electrophoresis were used.RESULTS AND DISCUSSION:For −308 polymorphism, 37 of 42 PANDAS patients’ results and for −850 C/T polymorphism, 38 of 42 PANDAS patients’ results were obtained. According to our statistical analysis there is a positive relationship between PANDAS patients for −308 G/A polymorphism but not for −850 C/T polymorphism. There is no positive relationship between −308 G/A polymorphism and antistrep-tolysin O (ASO) titers and no relationship between −850 C/T polymorphism and ASO titers. We found, however, positive relationship between genders of patients (boys) and the disease. According to our results, we propose that the AA polymorphism of −308 G/A polymorphism can be used as a molecular indicator for PANDAS.

Association Between Obsessive Compulsive Disorder And Tumor Necrosis Factor-Α Gene –308 (G&gt;A) And –850 (C&gt;T) Polymorphisms In Turkish Children

Obsessive compulsive disorder (OCD) is a neurobiological disease characterized with obsessions and compulsions. Obsessive compulsive disorder occurs with an autoimmune mechanism after Group A β hemolytic streptococcus (GABHS) infection. Tumor necrosis factor (TNF) is an important cytokine, as well as having an important role in the apoptosis mechanism of autoimmune diseases. It is expressed by the TNF-α gene. The aim of this study was to examine the relationship between the TNF-α gene promoter region −308 (G>A) and −850 (C>T) polymorphisms and OCD. In this study, ages of the OCD patients and the control group ranged between 4 and 12 years. We studied two patient groups, one included childhood onset OCD patients (n = 49) and the control group was composed of healthy children (n = 58). Patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria and with Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime (KSAD-S-PL) version. For identifying the polymorphisms, polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) and polyacrylamide gel electrophoresis (PAGE) methods were used.For the −308 polymorphism, 45 of 49 OCD patients’ results were completed, and for the −850 polymorphism, 47 of 49 OCD patients’ results were completed. According to our statistical results, there is a positive relationship between OCD and the −308 polymorphism (p <0.001) but no association between OCD and the −850 polymorphism (p = 0.053). There is no positive relationship between antistreptolysin O (ASO) titers and the −308 polymorphism (p = 0.953) but there is an important significance between the −850 polymorphism and ASO (p = 0.010). There is no positive relationship between gender of patients and OCD (p = 0.180) and no positive association between ASO and gender (p = 0.467). According to our results, we hypothesize that we can propose the mutant AA genotype for the −308 polymorphism, and that the mutant CT genotype for the −850 polymorphism may be used as molecular indicators for OCD.

Mechanism of TNF-α autocrine effects in hypoxic cardiomyocytes: Initiated by hypoxia inducible factor 1α, presented by exosomes

Excessive tumor necrosis factor-α (TNF-α) expression is increasingly thought to be detrimental to cardiomyocytes in acute myocardial infarction. During myocardial ischemia, TNF-α is mainly released from macrophages, but with persistent ischemia, it can originate from cardiomyocytes and contribute to cardiac remodeling. The initiating factor and exact molecular mechanism of TNF-α release from cardiomyocytes is presently unclear. In this study, we investigated direct effects of hypoxia on TNF-α expression of cardiomyocytes, the role of hypoxia inducible factor-1α (HIF-1α) in TNF-α regulation and potential secretory pathway of TNF-α. Elevated TNF-α expression and HIF-1α activation in primary cultured cardiomyocytes under hypoxia were detected by real-time PCR, Western blotting and immunofluorescence. TNF-α mRNA elevation and protein secretion were obviously inhibited by nucleofection of HIF-1α small interfering RNA (siRNA) and treatment with 2-methoxyestradiol (inhibitor of HIF-1α protein). Similar results were observed in HEK293 and HepG2 cells. Putative hypoxia response elements were identified in the human TNF-α gene promoter. Deletion analysis and site-directed mutagenesis demonstrated that HIF consensus binding sites spanning bp-1295 to bp-1292 relative to the transcription start site were functional for activation of the TNF-α promoter which was confirmed by electrophoretic mobility-shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis. Exosomes (vesicles mediating a non-classical route of protein secretion) in supernatants from hypoxic cardiomyocytes were identified by an anti-CD63 antibody in Western blot and observed by electron microscopy. The presence of TNF-α within exosomes precipitated from supernatants of hypoxic cardiomyocytes was verified by immunoelectron microscopy and immunoblotting. Results of this study indicate that under hypoxia, HIF-1α initiates expression of TNF-α, mediated by exosomes in cardiomyocytes.

Meta-Analysis Shows Strong Positive Association of the TNF-α Gene with Tumor Stage in Bladder Cancer

There is no consensus on the association between the tumor necrosis factor-α (TNF-α) gene promoter –308 A/G single nucleotide polymorphisms and bladder cancer risk. To obtain a more precise estimation of this correlation, we conducted a meta-analysis. The PubMed, MEDLINE, Cochrane Library and China National Knowledge Infrastructure (CNKI) databases were searched for relevant published studies. Seven case-control studies with a total of 1,311 cases and 1,436 controls were identified and analyzed. A notable correlation was observed between the TNF-α genotype and bladder cancer grade (AA+GA vs. GG; odds ratio 1.96, 95% confidence interval 1.37–2.80, p = 0.0002). In summary, this meta-analysis demonstrates that the TNF-α –308 AA+GA genotype may be a marker to the tumor-invasive stage of bladder cancer.

Influence of Polymorphism −308 G/A of the Tnf-α Gene on High Mobility Group Box-1 Protein in Rheumatoid and Spondylo-Arthritis Patients

Single nucleotide polymorphism (SNP) in the human Tumor Necrosis Factor-α(TNF-α) gene promoter, the −308 G/A variant, has been associated with increased TNF-α levels that may amplify the severity of rheumatoid arthritis (RA) and a poor responsiveness to TNF-α blockade therapy. High mobility group box protein (HMGB-1) is a pro-inflammatory cytokine that plays a pivotal role in the pathogenesis of RA and may be an original target of therapy. The aim of this study is to investigate whether the −308 G/A variant of the TNF-α gene is associated with altered expression of HMBG-1. A total of 110 consecutive patients with rheumatoid arthritis and spondylo-arthritis (ankylosing spondylitis, psoriatic arthritis and spondylitis associated with inflammatory bowel disease) referring to the Rheumatology Unit of Messina University Hospital were enrolled. Patients were genotyped for the −308 TNF-α gene promoter polymorphism. Clinical status was also assessed. HMGB-1 and TNF-α mRNA(Real Time PCR) from total blood and plasmatic HMGB-1 (Western Blot analysis) and TNF-α (ELISA) protein were also evaluated. Irrespective of the underlying disease, patients carrying the G/A genotype showed enhanced HMGB-1 and TNF-α mRNA levels and increased circulating concentration of the inflammatory cytokines when compared to patients with G/G genotype. The data suggest that subjects carrying the TNF-α −308G/A genotype have enhanced expression of HMGB-1 protein that may explain, at least in part, the increased severity of the disease.

Cyclophilin B Attenuates the Expression of TNF-α in Lipopolysaccharide-Stimulated Macrophages through the Induction of B Cell Lymphoma-3

Extracellular cyclophilin A (CyPA) and CyPB have been well described as chemotactic factors for various leukocyte subsets, suggesting their contribution to inflammatory responses. Unlike CyPA, CyPB accumulates in extracellular matrixes, from which it is released by inflammatory proteases. Hence, we hypothesized that it could participate in tissue inflammation by regulating the activity of macrophages. In the current study, we confirmed that CyPB initiated in vitro migration of macrophages, but it did not induce production of proinflammatory cytokines. In contrast, pretreatment of macrophages with CyPB attenuated the expression of inflammatory mediators induced by LPS stimulation. The expression of TNF-α mRNA was strongly reduced after exposure to CyPB, but it was not accompanied by significant modification in LPS-induced activation of MAPK and NF-κB pathways. LPS activation of a reporter gene under the control of TNF-α gene promoter was also markedly decreased in cells treated with CyPB, suggesting a transcriptional mechanism of inhibition. Consistent with this hypothesis, we found that CyPB induced the expression of B cell lymphoma-3 (Bcl-3), which was accompanied by a decrease in the binding of NF-κB p65 to the TNF-α promoter. As expected, interfering with the expression of Bcl-3 restored cell responsiveness to LPS, thus confirming that CyPB acted by inhibiting initiation of TNF-α gene transcription. Finally, we found that CyPA was not efficient in attenuating the production of TNF-α from LPS-stimulated macrophages, which seemed to be due to a modest induction of Bcl-3 expression. Collectively, these findings suggest an unexpected role for CyPB in attenuation of the responses of proinflammatory macrophages.

Tumor necrosis factor alpha promoter polymorphism −308 G/A in Brazilian patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of antibodies to components of the cell nucleus in association with a diverse array of clinical manifestations. Polymorphisms in cytokines genes may play an important role in the development and clinical manifestation. Due to this, there is a great interest in the identification of biomarkers that which could quantify the susceptibility and disease activity. A case-control study of 98 lupus cases and 76 lupus-free adults controls, was performed to analyze whether or not the polymorphism of the TNF-α gene promoter at positions -308 G/A would alter the risk for SLE and clinical manifestations. Genotyping was carried out by polymerase chain reaction, PCR products were digested by NcoI restriction enzyme and fractionated after on 2% Agarose gel and visualized posteriorly staining by ethidium bromide. There were significant differences in the distribution of the TNF-α gene polymorphism between the SLE and control groups. Individual carriers of the variant allele A had a 3.29 (95% CI: 1.7738-6.1325)-fold increased risk for SLE. Moreover, association was observed between SLE patients and serositis (P=0.0228). This study presents a preliminary evidence of association between TNF-α polymorphism and SLE susceptibility in the Northeast population from Brazil.

TNF-α-308 promoter G/A and PTPN22 (1858 C/T) genes polymorphisms in Egyptian patients with systemic lupus erythematosus

Tumor necrosis factor alpha (TNF-α) promoter gene polymorphism at position 308 and that of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) at position 1858 C/T have been inconsistently implicated as genetic risk factors for systemic lupus erythematosus (SLE) in some populations. We investigated the possible association of these polymorphisms with SLE susceptibility, and whether serum TNF-α level is related to different genotypes and disease activity in Egyptian SLE patients. TNF-α-308 G/A and PTPN22 C1858T polymorphisms were determined by PCR-restriction fragment length polymorphism analysis in 40 SLE patients and 40 unrelated healthy controls. Serum TNF-α level was measured by ELISA method. The median serum TNF-α was significantly higher in SLE patients than in controls (P < 0.001). A significant positive correlation was detected between serum TNF-α and SLE activity index (r = 0.723, P < 0.001). There was no significant difference in TNF-α-308 G/A genotypes or allele frequency between SLE cases and controls (P = 0.108 and P = 0.133, respectively). Diabetes was the only clinical feature in SLE patients that showed significant higher frequency with GA genotype than with GG genotype (P = 0.001). Risk estimation for the TNF-α-308 genotypes was of no significant (odds ratio = 2.429; 95 % CI = 0.8–7.2; P = 0.108). Concerning PTPN22 1858 C/T, there was no significant difference in PTPN22 C/T genotypes or allele frequency between SLE cases and controls (P = 0.152 and P = 0.155, respectively). TNF-α-308 G/A and PTPN22 (1858 C/T) polymorphisms do not exhibit a significant influence on the susceptibility of SLE in Egyptian patients. However, serum TNF-α level could be a sensitive marker of SLE disease activity.

Association of the tumor necrosis factor-alpha -1031T/C and its combination with interleukin-6 -634C/G gene polymorphisms with susceptibility to endometriosis

To investigate the association of tumor necrosis factor-alpha (TNF-α) gene promoter region -1031T/C and its combination with interleukin-6 (IL-6) gene promoter region -634C/G single nucleotide polymorphisms (SNP) with the genetic susceptibility to endometriosis. Total of 432 endometriosis patients and 499 non-endometriosis women who had received an operation due to tubal ligation, tubal recanalization, laparoscopic hydrotubation, ovarian simple cyst and teratoma were collected and separated into endometriosis group and control group, that all cases were confirmed by operation and pathology. A case-control study was performed in endometriosis and control group to evaluate the association of these SNP with the susceptibility to endometriosis by using a fluorescent quantitative PCR-based high resolution melting (HRM) method. (1) TNF-α -1031T/C genotype:the T and C of TNF-α -1031T/C allele frequencies in the endometriosis group and control group were 79.2% (684/864), 20.8% (180/864) and 81.8% (816/998), 18.2% (182/998), respectively. The TT, TC and CC of TNF-α -1031T/C genotype frequencies in the two groups were 63.7% (275/432), 31.0% (134/432), 5.3% (23/432) and 66.5% (332/499), 30.5% (152/499), 3.0% (15/499), respectively. There were no statistical significances in the TNF-α -1031T/C alleles and genotypes distributions between the two groups (P = 0.158, P = 0.186). (2) TNF-α -1031T/C and IL-6 -634C/G conjoint genotypes: to research on the TNF-α -1031T/C and IL-6 -634C/G genotypes for conjoint analysis, the TT+CC, TC+CC, CC+CC, TT+CG, TC+CG, CC+CG, TT+GG, TC+GG and CC+GG combination genotype frequencies in the two groups were 39.4% (170/432), 19.4% (84/432), 4.6% (20/432), 20.6% (89/432), 8.8% (38/432), 0.9% (4/432), 3.5% (15/432), 2.3% (10/432), 0.5% (2/432) and 36.7% (183/499), 17.4% (87/499), 1.4% (7/499), 26.1% (130/499), 10.4% (52/499), 1.2% (6/499), 3.8% (19/499), 2.6% (13/499), 0.4% (2/499), respectively. There were no statistical significances in the combination genotypes distributions between the two groups (P = 0.107). As compared with carriers of TT+CC combination genotype, the endometriosis risk of carriers of CC+CC combination genotype enhanced 3.076 times (95%CI: 1.268 - 7.457, P = 0.009), and the endometriosis risk of carriers of other combination genotypes were no statistical significances (all P > 0.05). The study demonstrates that there are no significant association between the SNP of TNF-α -1031T/C and genetic susceptibility to endometriosis. However the results indicate that there are significant association between genetic susceptibility to endometriosis and the combination polymorphisms of TNF-α -1031T/C and IL-6 -634C/G.

Lack of association between TNF-α gene promoter polymorphisms and pancreatitis: A meta-analysis

Background/AimsTumor necrosis factor alpha (TNF-α) is a major proinflammatory cytokine involved in the etiology of pancreatitis. The association between pancreatitis and the −308G>A and −238G>A polymorphisms in TNF-α gene has been analyzed in several studies, but results have been inconsistent. The purpose of this study was to integrate previous findings and explore whether these polymorphisms are associated with susceptibility and severity to pancreatitis. MethodsA meta-analysis was performed by searching PubMed, Cochrane Library, and ScienceDirect databases. Data were extracted using predefined form and odds ratios (OR) with 95% confidence intervals (CI) were calculated. ResultsOur meta-analysis of a total of 1569 pancreatitis cases and 1330 control subjects from twelve published case–control studies for the −308G>A polymorphism (OR 0.98; 95% CI 0.83–1.17), and of 480 cases and 302 controls from four studies for the −238G>A polymorphism (OR 0.92; 95% CI 0.58–1.47) did not show any significant associations of susceptibility to pancreatitis with the variant GA+AA genotypes compared with the GG genotype. An association between severity of acute pancreatitis and −308G>A polymorphism was not found either (OR 0.93; 95% CI 0.69–1.24). ConclusionPolymorphisms in two sites of TNF-α gene promoter do not alter the risk of pancreatitis.

Association of tumor necrosis factor‐α gene promoter polymorphism at sites ‐308 and ‐238 with non‐alcoholic fatty liver disease: A meta‐analysis

Environmental and genetic factors play a role in the pathogenesis and natural history of non-alcoholic fatty liver disease (NAFLD). The objective of this study was to quantitatively evaluate the association between tumor necrosis factor (TNF)-α gene promoter polymorphism at sites -308 and -238 and NAFLD susceptibility. We performed an extensive search of relevant studies and made a meta-analysis, including eight studies with 837 NAFLD cases and 990 controls in the association between TNF-α -308 polymorphism and NAFLD; and seven studies with 771 cases and 787 controls in TNF-α -238 polymorphism. The combined results showed that there was a significant difference in TNF-α-238 genotype distribution between NAFLD and control based on all studies (GA/AA vs GG [odds ratio = 2.06, 95% confidence interval = 1.58-2.69, P < 0.000,01]). However, the combined results based on all studies showed there was no evidence of association of TNF-α-308 genotype distribution between NAFLD cases and controls (GA/AA vs GG [odds ratio = 1.08, 95% confidence interval = 0.82-1.42, P = 0.60]). When stratifying for race, the significant results did not change materially compared with whole populations. This meta-analysis suggested that TNF-α gene promoter polymorphism at position -238 but not -308 might be a risk factor for NAFLD.

Association of TNF-α and Fas gene promoter polymorphism with the risk of Kashin–Beck disease in Northwest Chinese population

The objective of this study is to investigate the relationship between single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor-α (TNF-α) and Fas genes and Kashin-Beck disease (KBD) in Shaanxi province, Northwest in China. Blood samples of 388 residents were collected from 14 KBD villages in Linyou and Yongshou counties, Shaanxi, Northern of China. One hundred eighty-six cases with KBD and 202 cases of health in KBD areas were diagnosed by "Diagnosis Criterion of Kashin-Beck disease in China (WS/T207- 2010)". The TNF-α -308G/A, TNF-α -238G/A, and Fas -670A/G SNPs were determined by polymerase chain reaction-restriction fragment length polymorphism in combination with sequence analysis in KBD and healthy control groups. The genotypes and allele frequencies distribution of these SNPs were then analyzed. TNF-α -308A allele frequency in KBD patients were significantly higher than that in healthy controls. Although TNF-α -238 genotypes and allele frequencies were not significantly different between KBD patients and the healthy controls, GA genotype and A allele frequency in KBD patients were higher than those in healthy controls. The TNF-α -308G/A SNPs were associated with the susceptibility of KBD.

Association of tumor necrosis factor-α gene promoter polymorphisms (-308G/A, -238G/A) with recurrent spontaneous abortion: a meta-analysis

Tumor necrosis factor-α (TNF-α) gene promoter polymorphisms (-308G/A, -238G/A) have been associated with increased recurrent spontaneous abortion (RSA) risk, but the results of published articles are controversial. Hence, a meta-analysis was performed to assess the effect of TNF-α -308G/A, -238G/A polymorphisms on RSA risk. Heterogeneity testing and sensitivity analysis were performed using RevMan 5.0 software. Publication bias was assessed by the funnel plot method and modified Egger's linear regression test. In 12 studies for the TNF-α -308G/A polymorphism, the summary odds ratio (OR) with the corresponding 95% confidence interval (95% CI) was 1.04 (95% CI: 0.86, 1.26) under a fixed-effect model in the overall population. In 5 studies for the TNF-α -238G/A polymorphism, the summary OR with the corresponding 95% CI was 1.11 (95% CI: 0.60, 2.03) under a random-effect model in the overall population. We could not identify the sources of heterogeneity for TNF-α -238G/A. In addition, no evidence of publication bias was detected. The results of this meta-analysis indicate that TNF-α -308G/A, -238G/A polymorphisms are not significantly associated with the risk of RSA in the overall population. However, more convincing evidence is required to draw a solid conclusion on the relation between the TNF-α -238G/A polymorphism and the risk of RSA.

Effect of Prostaglandin I2 Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation

Prostaglandin I(2) (PGI(2)) analog is regarded as a potential candidate for treating asthma. Human myeloid dendritic cells (mDCs) play a critical role in the pathogenesis of asthma. However, the effects of PGI(2) analog on human mDCs are unknown. In the present study, circulating mDCs were isolated from six healthy subjects. The effects of PGI(2) analogs iloprost and treprostinil on cytokine production, maturation and T-cell stimulatory function of human mDCs were investigated. Tumor necrosis factor (TNF)-α and interleukin (IL)-10 were measured by enzyme-linked immunosorbent assay. The expression of costimulatory molecules was investigated by flow cytometry. T-cell stimulatory function was investigated by measuring interferon (IFN)-γ, IL-13 and IL-10 production by T cells cocultured with iloprost-treated mDCs. Intracellular signaling was investigated by Western blot and chromatin immunoprecipitation. We found that iloprost and treprostinil induced IL-10, but suppressed TNF-α production in polyinosinic-polycytidylic acid (poly I:C)-stimulated mDCs. This effect was reversed by the I-prostanoid (IP), E-prostanoid (EP) receptor antagonists or intracellular free calcium (Ca(2+)) chelator. Forskolin, an adenyl cyclase activator, conferred a similar effect. Iloprost and treprostinil increased intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels, and iloprost also increased intracellular Ca(2+). Iloprost suppressed poly I:C-induced mitogen-activated protein kinase (MAPK) phospho-p38 and phospho-activating transcription factor (ATF)2 expression. Iloprost downregulated poly I:C-induced histone H3K4 trimethylation in the TNFA gene promoter region via suppressing translocation of histone 3 lysine 4 (H3K4)-specific methyltransferases MLL (mixed lineage leukemia) and WDR5 (WD repeat domain 5). Iloprost-treated mDCs inhibited IL-13, IFN-γ and IL-10 production by T cells. In conclusion, PGI(2) analogs enhance IL-10 and suppress TNF-α expression through the IP/EP2/EP4 receptors-cAMP and EP1 receptor-Ca(2+) pathway. Iloprost suppressed TNF-α expression via the MAPK-p38-ATF2 pathway and epigenetic regulation by downregulation of histone H3K4 trimethylation.